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Analysis of cellular quality control in liver tissue formation

Research Project

Project/Area Number 26293012
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Biological pharmacy
Research InstitutionTokyo Medical and Dental University

Principal Investigator

NISHINA Hiroshi  東京医科歯科大学, 難治疾患研究所, 教授 (60212122)

Co-Investigator(Kenkyū-buntansha) 浅岡 洋一  東京医科歯科大学, 難治疾患研究所, 助教 (10436644)
Co-Investigator(Renkei-kenkyūsha) HIRAYAMA Jun  東京医科歯科大学, 難治疾患研究所, 准教授 (90510363)
MIYAMURA Norio  東京医科歯科大学, 難治疾患研究所, 助教 (10725493)
Research Collaborator KATADA Toshiaki  東京大学, 大学院薬学研究科, 教授
MIYAJIMA Atsushi  東京大学, 大学分子細胞生物学研究所, 教授
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Keywords肝臓 / シグナル / ストレス / 器官形成 / 障害 / モザイク解析 / Hippo / YAP / 細胞排除 / モデル生物 / メダカ / 肝発生 / 肝再生 / シグナル伝達 / Hippoシグナル / 品質管理 / PDZ結合ドメイン / 細胞増殖 / 細胞分化
Outline of Final Research Achievements

The presence of senescent, transformed, or damaged cells can impair tissue function or lead to tumorigenesis. However, how this quality control is regulated remains largely unclear. Here, using in vivo mosaic analysis in mouse liver, we show that YAP activation induced by inactivation of the Hippo pathway specifically in damaged hepatocytes induces their selective elimination. These damaged hepatocytes migrate into the hepatic sinusoids, undergo apoptosis, and are engulfed by Kupffer cells. This involves the activation of CDC42 and Rac to regulate cell migration. Thus, YAP acts as a stress sensor that induces the elimination of injured cells to maintain tissue and organ homeostasis.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report

Research Products

(28 results)

All 2016 2015 2014 Other

All Int'l Joint Research Journal Article Presentation Book Remarks

  • [Int'l Joint Research] IMBA(オーストリア)

    • Related Report
      2016 Annual Research Report
  • [Journal Article] The mevalonate pathway regulates primitive streak formation via protein farnesylation.2016

    • Author(s)
      Okamoto-Uchida Y, Yu R, Miyamura N, Arima N, Ishigami-Yuasa M, Kagechika H, Yoshida S, Hosoya T, Nawa M, Kasama T, Asaoka Y, Alois RW, Elling U, Penninger JM, Nishina S, Azuma N, Nishina H
    • Journal Title

      Scientific Reports.

      Volume: 6 Pages: 37697-37697

    • DOI

      10.1038/srep37697

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Active form of YAP expressing MDCK cells are extruded apically depending on neighboring cells status2016

    • Author(s)
      Chiba, T., Ishihara, E., Miyamura, N., Narumi, R., Kajita, M., Fujita, Y., Suzuki, A., Ogawa, Y. and *Nishina, H.
    • Journal Title

      SCIENTIFIC REPORT

      Volume: 10 Pages: 28383-28383

    • DOI

      10.1038/srep28383

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] SLC7 family transporters control the establishment of left-right asymmetry during organogenesis in medaka by activating mTOR signaling2016

    • Author(s)
      Asaoka Y, Nagai Y, Namae M, Furutani-Seiki M, Nishina H
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 474 Pages: 146-153

    • DOI

      10.1016/j.bbrc.2016.04.087

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Dysregulated YAP1/TAZ and TGFβ signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice2016

    • Author(s)
      Nishio, M., Sugimachi, K., Goto, H., Wang, J., Morikawa, T., Miyachi, Y., Takano, Y., Hikasa, H., Itoh, T., Suzuki, S.O., Kurihara, H., Aishima, S., Leask, A., Sasaki, T., Nakano, T., Nishina, H., Nishikawa, Y., Sekido, Y., Nakao, K., Shin-ya, K., Mimori, K. and Suzuki, A.
    • Journal Title

      Proc. Natl. Acad. Sci. USA

      Volume: 113 Pages: 71-80

    • DOI

      10.1073/pnas.1517188113

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genetically Encoded Fluorescent Probe for Imaging Apoptosis in vivo with Spontaneous GFP Complementation2016

    • Author(s)
      Yusuke Nasu, Yoichi Asaoka, Misako Namae, Hiroshi Nishina, Hideaki Yoshimura and Takeaki Ozawa
    • Journal Title

      Anal. Chem.

      Volume: 88 Pages: 834-844

    • DOI

      10.1021/acs.analchem.5b03367

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Validation of chemical compound library screening for transcriptional co-activator with PDZ-binding motif inhibitors using GFP-fused transcriptional co-activator with PDZ-binding motif.2016

    • Author(s)
      Nagashima S, Maruyama J, Kawano S, Iwasa H, Nakagawa K, Ishigami-Yuasa M, Kagechika H, Nishina H, Hata Y.
    • Journal Title

      Cancer science

      Volume: - Pages: 791-802

    • DOI

      10.1111/cas.12936

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Modulation of anti-cancer drug sensitivity through the regulation of mitochondrial activity by adenylate kinase 42016

    • Author(s)
      Fujisawa K, Terai S, Takami T, Yamamoto N, Yamasaki T, Matsumoto T, Yamaguchi K, Owada Y, Nishina H, Noma T, Sakaida I.
    • Journal Title

      J. Exp. Clin. Cancer Res.

      Volume: - Pages: 0322-0324

    • DOI

      10.1186/s13046-016-0322-2

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A Modified Murine Embryonic Stem Cell Test for Evaluating the Teratogenic Effects of Drugs on Early Embryogenesis.2015

    • Author(s)
      Ruoxing Yu, Norio Miyamura, Yoshimi Okamoto-Uchida, Norie Arima, Mari Ishigami-Yuasa, Hiroyuki Kagechika and Hiroshi Nishina
    • Journal Title

      PLoS One.

      Volume: 10

    • DOI

      10.1371/journal.pone.0145286

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] YAP is essential for tissue tension to ensure vertebrate 3D body shape.2015

    • Author(s)
      Sean Porazinski, Huijia Wang, Yoichi Asaoka, Martin Behrndt, Tatsuo Miyamoto, Hitoshi Morita, Shoji Hata et al.
    • Journal Title

      NATURE

      Volume: 印刷中 Pages: 217-221

    • DOI

      10.1038/nature14215

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The Hippo pathway controls a switch between retinal progenitor cell proliferation and photoreceptor cell differentiation in zebrafish.2014

    • Author(s)
      Yoichi Asaoka, Shoji Hata, Misako Namae, Makoto Furutani-Seiki and Hiroshi Nishina
    • Journal Title

      PLoS ONE

      Volume: 9

    • DOI

      10.1371/journal.pone.0097365

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity2014

    • Author(s)
      Shimomura T, Miyamura N, H ata S, Miura R, Hirayama J, N ishina H
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 443 Pages: 206-210

    • DOI

      10.1016/j.bbrc.2013.12.100

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Screening with a novel cell-based assay for TAZ activators identifies a compound that enhances myogenesis in C2C12 cells and facilitates muscle repair in a muscle injury model.2014

    • Author(s)
      Yang, Z. Y.; Nakagawa, K.; Sarkar, A.; Maruyama, J.; Iwasa, H.; Bao, Y. J.; Ishigami-Yuasa, M.; Ito, S.; Kagechika, H.; Hata, S.; Nishina, H.; Abe, S.; Kitagawa, M.; Hata, Y.
    • Journal Title

      Mol. Cell Biol.

      Volume: 34 Pages: 1607-1621

    • DOI

      10.1128/mcb.01346-13

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Overexpression of autotaxin, a lysophosphatidic acid-producing enzyme, enhances cardia bifida induced by hypo-sphingosine-1- phosphate signaling in zebrafish embryo2014

    • Author(s)
      Nakanaga K, Hama K, Kano K, Sato T, Yukiura H, Inoue A, Saigusa D, Tokuyama H, Tomioka Y, Nishina H, Kawahara A, Aoki J
    • Journal Title

      Journal of biochemistry

      Volume: 155 Pages: 235-241

    • DOI

      10.1093/jb/mvt114

    • NAID

      40020035029

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Status and prospects of liver cirrhosis treatment by using bone marrow-derived cells and mesenchymal cells2014

    • Author(s)
      Terai S, Takami T, Yamamoto N, Fujisawa K, Ishikawa T, Urata Y, Tanimoto H, Iwamoto T, Mizunaga Y, Matsuda T, Oono T, Marumoto M, Burganova G, Fernando Quintanilha L, Hidaka I, Marumoto Y, Saeki I, Uchida K, Yamasaki T, Tani K, Taura Y, Fujii Y, Nishina H, Okita K, Sakaida I.
    • Journal Title

      Tissue Eng Part B Rev.

      Volume: 20(3) Pages: 206-210

    • DOI

      10.1089/ten.teb.2013.0527

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] 器官形成におけるHippo-YAPシグナル伝達経路の役割-幹細胞・前駆細胞の分化制御2016

    • Author(s)
      仁科博史
    • Organizer
      第89回日本生化学大会
    • Place of Presentation
      仙台
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 器官の3D構築とサイズの制御2016

    • Author(s)
      仁科博史
    • Organizer
      第7回Molecular Cardiovascular Conference
    • Place of Presentation
      東京
    • Year and Date
      2016-09-02
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] メダカに学ぶ再生医療の基礎2016

    • Author(s)
      仁科博史
    • Organizer
      第15回公開市民講座
    • Place of Presentation
      東京都文京区
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 3D器官構築を制御するHippo-YAPシグナル伝達経路2015

    • Author(s)
      仁科博史
    • Organizer
      9th: Metabolic Research Cutting Edge
    • Place of Presentation
      第一三共本社(東京)
    • Year and Date
      2015-10-10
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 脊椎動物3D器官形成を制御するHippo-YAPシグナル伝達経路2015

    • Author(s)
      仁科博史
    • Organizer
      日本Cell Death学会
    • Place of Presentation
      大阪大学(大阪)
    • Year and Date
      2015-07-11
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] The Hippo pathway controls a switch between retinal progenitor cell proliferation and photoreceptor cell differentiation in zebrafish2015

    • Author(s)
      Hiroshi Nishina
    • Organizer
      2015 Keystone Symposia The Hippo Pathway: Signaling, Development and Disease
    • Place of Presentation
      New Mexico(米国)
    • Year and Date
      2015-05-17
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] がん原遺伝子産物YAP依存的肝細胞消失を誘導する新規マウスモデルの確立2014

    • Author(s)
      仁科博史
    • Organizer
      第37回日本分子生物学会
    • Place of Presentation
      横浜、パシフィコ
    • Year and Date
      2014-11-25 – 2014-11-27
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 成体マウス肝臓においてモザイク状のHippoシグナル伝達系破綻は細胞排除を誘導する2014

    • Author(s)
      仁科博史
    • Organizer
      第87回日本生化学会大会
    • Place of Presentation
      京都、国際会議場
    • Year and Date
      2014-10-15 – 2014-10-18
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 器官サイズを制御する転写共役因子YAPの役割2014

    • Author(s)
      仁科博史
    • Organizer
      第23回日本Cell Death学会
    • Place of Presentation
      東京、東京医科歯科大学M&Dタワー
    • Year and Date
      2014-07-18 – 2014-07-19
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Book] 発生・器官形成、がん悪性化に関わるHippoシグナル-創薬標的として高まるYAP/TAZへの期待2015

    • Author(s)
      仁科博史
    • Total Pages
      133
    • Publisher
      羊土社
    • Related Report
      2015 Annual Research Report
  • [Remarks] 「異常な細胞の除去を誘導する新たな仕組みの解明に成功」 ― がんの予防的治療法の開発に期待 ―

    • URL

      http://www.tmd.ac.jp/archive-tmdu/kouhou/20160621_2.pdf

    • Related Report
      2016 Annual Research Report
  • [Remarks] 発生初期の器官形成の鍵となる組織の分化に必要な代謝経路の解明

    • URL

      http://www.tmd.ac.jp/archive-tmdu/kouhou/20161124.pdf

    • Related Report
      2016 Annual Research Report
  • [Remarks] 東京医科歯科大学難治疾患研究所 発生再生生物学分野

    • URL

      http://www.tmd.ac.jp/mri/dbio/index.html

    • Related Report
      2015 Annual Research Report

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Published: 2014-04-04   Modified: 2018-03-22  

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